The Molecular Genetics Section has sought to elucidate functions of peptide growth factors and their tyrosine kinase receptors in oncogenesis and embryogenesis, by determining the consequences of subverting the normal regulation of those functions through the generation and analysis of relevant genetically engineered mouse models. Ubiquitous overexpression of hepatocyte growth factor/scatter factor (HGF/SF) resulted in the appearance of a remarkably wide variety of tumors of both mesenchymal and epithelial origin in transgenic mice. Typically, these tumors had elevated expression of HGF/SF, enhanced kinase activity of its protooncoprotein receptor, c-Met, and the associated creation of autocrine signal transduction loops. Among the tumors to which these transgenic mice were prediposed was malignant melanoma, which is normally very rare in mice. Moreover, 20% of mice bearing melanoma demonstrated metastic spread, prompting us to use this model to determine the role of the HGF/SF-Met signaling pathway in progression in melanoma. In addition, we have determined that melanocyte development was aberrant both in these mice overexpressing HGF/SF, and in mice carrying inactivating mutations in both alleles of c-met. These results indicate that c-met is essential for the normal development of melanocytes and plays an important role in their neoplastic transformation. Members of the fibroblast growth factor (FGF) superfamily and their receptors (FGFR) have been implicated as regulators of organ development based on their embryonic expression patterns and a variety of in vitro experiments. However, inactivation of individual genes encoding specific FGFs, or their receptors, has failed to demonstrate their role in organogenesis due to functional redundancy or early embryonic lethality. We have found that ubiquitous midgestational expression of a novel secreted kinase-deficient receptor, specific for a subset of the FGF superfamily, caused agenesis or severe dysgenesis of kidney, lung, specific cutaneous structures, exocrine and endocrine glands, as well as craniofacial and limb abnormalities reminiscent of human skeletal disorders associated with FGRF mutations. Analysis of diagnostic molecular markers revealed that this soluble dominant negative mutant disrupted early inductive signaling in affected tissues, strongly supporting the conclusion that FGF signaling is required for growth and patterning in a broad array of organs and in limbs.